New compounds, their preparation and use

ABSTRACT

The present invention relates to compounds of the general formula I.  
     The compounds are useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. 119 of Danishapplication No. PA 2000 00650 filed on Apr. 17, 2000, and U.S.provisional application No. 60/201,068 filed on May 1, 2000, thecontents of which are fully incorporated herein by reference.

FIELD OF INVENTION

[0002] The present invention relates to novel compounds, pharmaceuticalcompositions containing them, methods for preparing the compounds andtheir use as medicaments. More specifically, compounds of the inventioncan be utilised in the treatment and/or prevention of conditionsmediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR).

BACKGROUND OF THE INVENTION

[0003] Coronary artery disease (CAD) is the major cause of death in Type2 diabetic and metabolic syndrome patients (i.e. patients that fallwithin the ‘deadly quartet’ category of impaired glucose tolerance,insulin resistance, hypertriglyceridaemia and/or obesity).

[0004] The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content. Fibrates, on the one hand, are PPARα activators,acting primarily in the liver. Thiazolidinediones, on the other hand,are high affinity ligands for PPARγ acting primarily on adipose tissue.

[0005] Adipose tissue plays a central role in lipid homeostasis and themaintenance of energy balance in vertebrates. Adipocytes store energy inthe form of triglycerides during periods of nutritional affluence andrelease it in the form of free fatty acids at times of nutritionaldeprivation. The development of white adipose tissue is the result of acontinuous differentiation process throughout life. Much evidence pointsto the central role of PPARγ activation in initiating and regulatingthis cell differentiation. Several highly specialised proteins areinduced during adipocyte differentiation, most of them being involved inlipid storage and metabolism. The exact link from activation of PPARγ tochanges in glucose metabolism, most notably a decrease in insulinresistance in muscle, has not yet been clarified. A possible link is viafree fatty acids such that activation of PPARγ induces LipoproteinLipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoASynthetase (ACS) in adipose tissue but not in muscle tissue. This, inturn, reduces the concentration of free fatty acids in plasmadramatically, and due to substrate competition at the cellular level,skeletal muscle and other tissues with high metabolic rates eventuallyswitch from fatty acid oxidation to glucose oxidation with decreasedinsulin resistance as a consequence.

[0006] PPARα is involved in stimulating β-oxidation of fatty acids. Inrodents, a PPARα-mediated change in the expression of genes involved infatty acid metabolism lies at the basis of the phenomenon of peroxisomeproliferation, a pleiotropic cellular response, mainly limited to liverand kidney and which can lead to hepatocarcinogenesis in rodents. Thephenomenon of peroxisome proliferation is not seen in man. In additionto its role in peroxisome proliferation in rodents, PPARα is alsoinvolved in the control of HDL cholesterol levels in rodents and humans.This effect is, at least partially, based on a PPARα-mediatedtranscriptional regulation of the major HDL apolipoproteins, apo A-I andapo A-II. The hypotriglyceridemic action of fibrates and fatty acidsalso involves PPARα and can be summarised as follows: (I) an increasedlipolysis and clearance of remnant particles, due to changes inlipoprotein lipase and apo C-III levels, (II) a stimulation of cellularfatty acid uptake and their subsequent conversion to acyl-CoAderivatives by the induction of fatty acid binding protein and acyl-CoAsynthase, (III) an induction of fatty acid β-oxidation pathways, (IV) areduction in fatty acid and triglyceride synthesis, and finally (V) adecrease in VLDL production. Hence, both enhanced catabolism oftriglyceride-rich particles as well as reduced secretion of VLDLparticles constitutes mechanisms that contribute to the hypolipidemiceffect of fibrates.

[0007] A number of compounds have been reported to be useful in thetreatment of hyperglycemia, hyperlipidemia and hypercholesterolemia(U.S. Pat. No. 5,306,726, PCT Publications nos. W091/19702, WO 95/03038,WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO95/17394, WO 99/08501, WO 99/19313 and WO 99/16758).

SUMMARY OF THE INVENTION

[0008] Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia.

[0009] The clinical activity of fibrates and thiazolidinedionesindicates that research for compounds displaying combined PPARα andPPARγ activation should lead to the discovery of efficacious glucose andtriglyceride lowering drugs that have great potential in the treatmentof Type 2 diabetes and the metabolic syndrome (i.e. impaired glucosetolerance, insulin resistance, hypertriglyceridaemia and/or obesity).

DETAILED DESCRIPTION OF THE INVENTION

[0010] Accordingly, the present invention relates to compounds of thegeneral formula (I):

[0011] wherein

[0012] R¹, R², R³ and R⁴ independently of each other are hydrogen,C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl or C₁₋₆-alkoxyC₁₋₆-alkyl, optionally substituted with oneor more halogen, hydroxy or amino; and

[0013] x₁, x₂, X₃ and x₄ independently of each other is carbon, oxygen,sulphur or nitrogen; and

[0014] Y is C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, aralkyl,alkylaralkyl, hereroaryl, heteroaralkyl, or alkylheteroaralkyl,optionally substituted with one or more halogen, hydroxy or amino; and

[0015] Ar¹ and Ar² independently of each other are aryl or heteroaryloptionally substituted with one or more halogen, hydroxy, amino,aminoalkyl, carboxyalkyl, C₁₋₆-alkyl or C₁₋₆-alkoxy; or a salt thereofwith a pharmaceutically acceptable acid or base, or any optical isomeror mixture of optical isomers, including a racemic mixture, or anytautomeric forms.

[0016] Preferred compounds of the invention are:

[0017] Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionate,

[0018]2-Ethoxy-3-(4-(4-(4-(2-ethoxy-2-hydroxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionicacid,

[0019] Ethyl2-ethoxy-3-(4-(4-((4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-methyl)-benzyloxy)-phenyl)-propionate,

[0020] Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-ynyloxy)-phenyl)-propionate,

[0021]2-Ethoxy-3-(4-(4-((4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-methyl)-benzyloxy)-phenyl)-propionicacid,

[0022]2-Ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-ynyloxy)-phenyl)-propionicacid;

[0023] or a salt thereof with a pharmaceutically acceptable acid orbase, or any optical isomer or mixture of optical isomers, including aracemic mixture, or any tautomeric forms.

[0024] In the above structural formulas and throughout the presentspecification, the following terms have the indicated meaning:

[0025] The term “C_(1-n′)-alkyl” wherein n′ can be from 2 through 12, asused herein, represents a branched or straight or cyclic alkyl grouphaving from one to the specified number of carbon atoms. Examples ofsuch groups include, but are not limited to methyl, ethyl, n-propyl,isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl andthe like and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl and the like.

[0026] The terms “C_(2-n′)-alkenyl” wherein n′ can be from 3 through 12,as used herein, represents an olefinically unsaturated branched orstraight group having from 2 to the specified number of carbon atoms andat least one double bond. Examples of such groups include, but are notlimited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso-proppenyl,1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.

[0027] The terms “C_(2-n′)-alkynyl” wherein n′ can be from 3 through 12,as used herein, represent an unsaturated branched or straight grouphaving from 2 to the specified number of carbon atoms and at least onetriple bond. Examples of such groups include, but are not limited to,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl andthe like.

[0028] The term “C₁₋₆-alkoxy” as used herein, alone or in combination isintended to include those C₁₋₆-alkyl groups of the designated length ineither a linear or branched or cyclic configuration linked thorugh anether oxygen having its free valence bond from the ether oxygen.Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy and the like. Examples of branched alkoxy are isoprpoxy,sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like. Examples ofcyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy and the like.

[0029] The term “C₁₋₆-alkoxyC₁₋₆-alkyl” as used herein, alone or incombination, refers to a C₁₋₆-alkyl as defined herein whereto isattached a C₁₋₆-alkoxy as defined herein, e.g. methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

[0030] The term “aryl” is intended to include aromatic rings, such ascarboxylic aromatic rings selected from the group consisting of phenyl,naphthyl, (1-naphtyl or 2-naphtyl) and the like optionally substitutedwith halogen, amino, hydroxy, C₁₋₆alkyl or C₁₋₆-alkoxy and the like.

[0031] The term “halogen” means fluorine, chlorine, bromine or iodine.

[0032] The term “heteroaryl” as used herein, alone or in combination,refers to a monovalent substituent comprising a 5-6 membered monocyclicaromatic system or a 9-10 membered bicyclic aromatic system containingone or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g.furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine,pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole,oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline,quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine andthe like.

[0033] The term “arylalkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with an aromatic carbohydride; such as benzyl, phenethyl,3-phenylpropyl, 1-naphtylmethyl, 2-(1-naphtyl)ethyl and the like.

[0034] The term “heteroarylalkyl” as used herein refers to a straight orbranched saturated carbon chain containing from 1 to 6 carbonssubstituted with a heteroaryl group; such as (2-furyl)methyl,(3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like.

[0035] Certain of the above defined terms may occur more than once inthe above formula (I), and upon such occurence each term shall bedefined independently of the other.

[0036] The present invention also encompasses pharmaceuticallyacceptable salts of the present compounds. Such salts includepharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable base addition salts, pharmaceutically acceptable metal salts,ammonium and alkylated ammonium salts. Acid addition salts include saltsof inorganic acids as well as organic acids. Representative examples ofsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic,phosphoric, sulfuric, nitric acids and the like. Representative examplesof suitable organic acids include formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric,pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic,citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium salts and the like. Examples of ammonium and alkylatedammonium salts include ammonium, methylammonium, dimethylammonium,trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium,butylammonium, tetramethylammonium salts and the like. Examples oforganic bases include lysine, arginine, guanidine, diethanolamine,choline and the like.

[0037] The pharmaceutically acceptable salts are prepared by reactingthe compound of formula I with 1 to 4 equivalents of a base such assodium hydroxide, sodium methoxide, sodium hydride, potassiumt-butoxide, calcium hydroxide, magnesium hydroxide and the like, insolvents lilke ether, THF, methanol, t-butanol, dioxane, isopropanol,ethanol etc. Mixture of solvents may be used. Organic bases like lysine,arginine, diethanolamine, choline, guandine and their derivatives etc.may also be used. Alternatively, acid addition salts whereeverapplicable are prepared by treatment with acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid,maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid,palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid,tartaric acid and the like in solvents like ethyl acetate, ether,alcohols, acetone, THF, dioxane etc. Mixture of solvents may also beused.

[0038] The stereoisomers of the compounds forming part of this inventionmay be prepared by using reactants in their single enantiomeric form inthe process wherever possible or by conducting the reaction in thepresence of reagents or catalysts in their single enantiomer form or byresolving the mixture of stereoisomers by conventional methods. Some ofthe preferred methods include use of microbial resolution, resolving thediastereomeric salts formed with chiral acids such as mandelic acid,camphorsulfonic acid, tartaric acid, lactic acid, and the like whereverapplicable or chiral bases such as brucine, cinchona alkaloids and theirderivatives and the like. Commonly used methods are compiled by Jaqueset al in “Enantiomers, Racemates and Resolution” (Wiley Interscience,1981). More specifically the compound of formula I may be converted to a1:1 mixture of diastereomeric amides by treating with chiral amines,amino acids, amino alcohols derived from amino acids; conventionalreaction conditions may be employed to convert acid into an amide; thediastereomers may be separated either by fractional crystallization orchromatography and the stereoisomers of compound of formula I may beprepared by hydrolysing the pure diastereomeric amide.

[0039] Various polymorphs of compound of general formula I forming partof this invention may be prepared by crystallization of compound offormula I under different conditions. For example, using differentsolvents commonly used or their mixtures for recrystallization;crystallizations at different temperatures; various modes of cooling,ranging from very fast to very slow cooling during crystallizations.Polymorphs may also be obtained by heating or melting the compoundfollowed by gradual or fast cooling. The presence of polymorphs may bedetermined by solid probe nmr spectroscopy, ir spectroscopy,differential scanning calorimetry, powder X-ray diffraction or suchother techniques.

[0040] Furthermore, the present compounds of formula I can be utilisedin the treatment and/or prevention of conditions mediated by nuclearreceptors, in particular the Peroxisome Proliferator-Activated Receptors(PPAR).

[0041] The invention also encompasses prodrugs of the present compounds,which on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of the present compounds,which are readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0042] The invention also encompasses active metabolites of the presentcompounds.

[0043] In a further aspect, the present invention relates to a method oftreating and/or preventing Type I or Type II diabetes, preferably TypeII diabetes.

[0044] In a still further aspect, the present invention relates to theuse of one or more compounds of the general formula I orpharmaceutically acceptable salts thereof for the preparation of amedicament for the treatment and/or prevention of Type I or Type IIdiabetes, preferably Type II diabetes.

[0045] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of IGT.

[0046] In a still further aspect, the present compounds are useful forthe treatment and/or prevention of Type 2 diabetes.

[0047] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from IGT to Type 2diabetes.

[0048] In a still further aspect, the present compounds are useful forthe delaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

[0049] In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

[0050] In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, hyperlipidemia, coronary artery disease, myocardialischemia and other cardiovascular disorders.

[0051] In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

[0052] In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomeruloscierosis, nephrotic syndrome, hypertensive nephrosclerosis.

[0053] In still another aspect, the present compounds may also be usefulfor improving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

[0054] The invention also relates to pharmaceutical compositionscomprising, as an active ingredient, at least one compound of theformula I or any optical or geometric isomer or tautomeric form thereofincluding mixtures of these or a pharmaceutically acceptable saltthereof together with one or more pharmaceutically acceptable carriersor diluents.

[0055] Furthermore, the invention relates to the use of compounds of thegeneral formula I or their tautomeric forms, their stereoisomers, theirpolymorphs, their pharmaceutically acceptable salts or pharmaceuticallyacceptable solvates thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of conditions mediatedby nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR) such as the conditions mentionedabove.

[0056] The present invention also relates to a process for thepreparation of the above said novel compounds, their derivatives, theiranalogs, their tautomeric forms, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

[0057] A compound of formula I can be prepared as described below:

[0058] Reacting two molecules of a compound of formula II with onemolecule of a compound of formula III, wherein R¹, R⁴, Ar¹, x₁, x₂ and Yare as described above, with the exception that x₂ is not carbon and R¹is not hydrogen, and L is a leaving group like halogen, mesyloxy orhydroxy under Mitsunobo conditions

[0059]  to give a compound of formula I with R¹═R² and R⁴═R³,

[0060] or by reacting one molecule of a compound of formula II with onemolecule of a compound of formula III, followed by a reaction of thegenerated compound of formula IV with a compound of formula V, whereinR¹, R², R³, R⁴, Ar¹, Ar², x₁, x₂, x₃, x₄ and Y are as described above,with the exception that x₂ and x₃ are not carbon and R¹ and R² are nothydrogen, and L is a leaving group like halogen, mesyloxy or hydroxy,under Mitsunobu conditions,

[0061]  to give a compound of formula I,

[0062] or hydrolyse the compound of formula I with R¹ and R² differentfrom hydrogen, to give a compound of formula I with R¹═R²═hydrogen.

Pharmacological Methods

[0063] In vitro PPAR alpha and PPAR gamma activation activity.

[0064] Principle

[0065] The PPAR gene transcription activation assays were based ontransient transfection into human HEK293 cells of two plasmids encodinga chimeric test protein and a reporter protein respectively. Thechimeric test protein was a fusion of the DNA binding domain (DBD) fromthe yeast GAL4 transcription factor to the ligand binding domain (LBD)of the human PPAR proteins. The PPAR LBD harbored in addition to theligand binding pocket also the native activation domain (activatingfunction 2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will force the fusionprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand, luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

[0066] Methods

[0067] Cell culture and transfection: HEK293 cells were grown inDMEM+10% FCS, 1% PS. Cells were seeded in 96-well plates the day beforetransfection to give a confluency of 80% at transfection. 0.8 μg DNA perwell was transfected using FuGene transfection reagent according to themanufacturers instructions (Boehringer-Mannheim). Cells were allowed toexpress protein for 48 h followed by addition of compound.

[0068] Plasmids: Human PPAR α and γ was obtained by PCR amplificationusing cDNA templates from liver, intestine and adipose tissuerespectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. TheLBD from each isoform PPAR was generated by PCR (PPARα: aa 167-C-term;PPARγ: aa 165-C-term) and fused to GAL4-DBD by subcloning fragments inframe into the vector pM1 generating the plasmids pM1αLBD and pM1γLBD.Ensuing fusions were verified by sequencing. The reporter wasconstructed by inserting an oligonucleotide encoding five repeats of theGal4 recognition sequence into the pGL2 vector (Promega).

[0069] Compounds: All compounds were dissolved in DMSO and diluted1:1000 upon addition to the cells. Cells were treated with compound(1:1000 in 200 μl growth medium including delipidated serum) for 24 hfollowed by luciferase assay.

[0070] Luciferase assay: Medium including test compound was aspiratedand 100 μl PBS incl. 1 mM Mg++ and Ca++ was added to each well. Theluciferase assay was performed using the LucLite kit according to themanufacturers instructions (Packard Instruments). Light emission wasquantified by counting SPC mode on a Packard Instruments top-counter.

Pharmaceutical Compositions

[0071] In another aspect, the present invention includes within itsscope pharmaceutical compositions comprising, as an active ingredient,at least one of the compounds of the general formula I or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

[0072] The present compounds may also be administered in combinationwith one or more further pharmacologically active substances eg.selected from antiobesity agents, antidiabetics, antihypertensiveagents, agents for the treatment and/or prevention of complicationsresulting from or associated with diabetes and agents for the treatmentand/or prevention of complications and disorders resulting from orassociated with obesity.

[0073] Thus, in a further aspect of the invention the present compoundsmay be administered in combination with one or more antiobesity agentsor appetite regulating agents.

[0074] Such agents may be selected from the group consisting of CART(cocaine amphetamine regulated transcript) agonists, NPY (neuropeptideY) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR β agonists.

[0075] In one embodiment of the invention the antiobesity agent isleptin.

[0076] In another embodiment the antiobesity agent is dexamphetamine oramphetamine.

[0077] In another embodiment the antiobesity agent is fenfluramine ordexfenfluramine.

[0078] In still another embodiment the antiobesity agent is sibutramine.

[0079] In a further embodiment the antiobesity agent is orlistat.

[0080] In another embodiment the antiobesity agent is mazindol orphentermine.

[0081] Suitable antidiabetics comprise insulin, GLP-1 (glucagon likepeptide-1) derivatives such as those disclosed in WO 98/08871 to NovoNordisk A/S, which is incorporated herein by reference as well as orallyactive hypoglycaemic agents.

[0082] The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the β-cells.

[0083] In one embodiment of the invention the present compounds areadministered in combination with insulin.

[0084] In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

[0085] In another embodiment the present compounds are administered incombination with a biguanide eg. metformin.

[0086] In yet another embodiment the present compounds are administeredin combination with a meglitinide eg. repaglinide.

[0087] In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor eg. miglitol or acarbose.

[0088] In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

[0089] Furthermore, the present compounds may be administered incombination with nateglinide.

[0090] In still another embodiment the present compounds areadministered in combination with an antihyperlipidemic agent orantilipidemic agent eg. cholestyramine, colestipol, clofibrate,gemfibrozil, lovastatin, pravastatin, simvastatin, probucol ordextrothyroxine.

[0091] In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, insulin, insulin and lovastatin, etc.

[0092] Furthermore, the present compounds may be administered incombination with one or more antihypertensive agents. Examples ofantihypertensive agents are β-blockers such as alprenolol, atenolol,timolol, pindolol, propranolol and metoprolol, ACE (angiotensinconverting enzyme) inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, quinapril and ramipril, calcium channel blockerssuch as nifedipine, felodipine, nicardipine, isradipine, nimodipine,diltiazem and verapamil, and α-blockers such as doxazosin, urapidil,prazosin and terazosin. Further reference can be made to Remington: TheScience and Practice of Pharmacy, 19^(th) Edition, Gennaro, Ed., MackPublishing Co., Easton, Pa., 1995.

[0093] It should be understood that any suitable combination of thecompounds according to the invention with one or more of theabove-mentioned compounds and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present invention.

[0094] Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington: The Science and Practise of Pharmacy, 19^(th) Ed., 1995.The compositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

[0095] Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

[0096] The pharmaceutical compositions can be sterilized and mixed, ifdesired, with auxiliary agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or colouring substances and the like,which do not deleteriously react with the active compounds.

[0097] The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

[0098] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

[0099] For nasal administration, the preparation may contain a compoundof formula I dissolved or suspended in a liquid carrier, in particularan aqueous carrier, for aerosol application. The carrier may containadditives such as solubilizing agents, e.g. propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabenes.

[0100] For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

[0101] Tablets, dragees, or capsules having talc and/or a carbohydratecarrier or binder or the like are particularly suitable for oralapplication. Preferable carriers for tablets, dragees, or capsulesinclude lactose, corn starch, and/or potato starch. A syrup or elixircan be used in cases where a sweetened vehicle can be employed.

[0102] A typical tablet which may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free compound or saltthereof) 5 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose,microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mgMagnesium stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 Tapprox. 0.9 mg

[0103] The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar. Such mammals include also animals, both domestic animals,e.g. household pets, and nondomestic animals such as wildlife.

[0104] The compounds of the invention are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per daymay be used. A most preferable dosage is about 0.1 mg to about 70 mg perday. In choosing a regimen for patients it may frequently be necessaryto begin with a dosage of from about 2 to about 70 mg per day and whenthe condition is under control to reduce the dosage as low as from about0.1 to about 10 mg per day. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

[0105] Generally, the compounds of the present invention are dispensedin unit dosage form comprising from about 0.1 to about 100 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage.

[0106] Usually, dosage forms suitable for oral, nasal, pulmonary ortransdermal administration comprise from about 0.001 mg to about 100 mg,preferably from about 0.01 mg to about 50 mg of the compounds of formulaI admixed with a pharmaceutically acceptable carrier or diluent.

[0107] Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

[0108] The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, whichhowever, are not to be construed as limiting.

[0109] The structures of the compounds are confirmed by either elementalanalysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry(MS). NMR shifts (δ) are given in parts per million (ppm) and onlyselected peaks are given. mp is melting point and is given in ° C.Column chromatography was carried out using the technique described byW. C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel60 (Art 9385). Compounds used as starting materials are either knowncompounds or compounds which can readily be prepared by methods knownper se.

[0110] Abbrevations: TLC thin layer chromatography DMSOdimethylsulfoxide CDCl₃ deutorated chloroform DMF N,N-dimethylformamidemin minutes h hours

Example 1

[0111]

[0112] Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionate.

[0113] To a solution of 2-buten-1,4-diol (0.5 mmol, 45 mg) in THF (15ml) was added triphenylphosphine (1.5 mmol, 393 mg). The reactionmixture was cooled to 0° C. and diethyl azodicarboxylate (1.5 mmol, 261mg) was added drop wise, followed by addition of a solution of ethyl3-(4-hydroxyphenyl)-2-ethoxy-propionicacid (2.0 mmol, 477 mg) in THF (2ml). The reaction was stirred at 0° C. for 2 hours and at roomtemperature for 8 days. Water was added and the mixture extracted withmethylene chloride (2×25 ml). The combined organic phases were dried andevaporated to give the crude title compound. Purification on columnchromatography using methylenechloride: ethyl acetate (5:1) gave thepure title compound in 109 mg (41%) yield. ¹H-NMR δ (CDCl₃) 7.15 (d,4H), 6.84 (d, 4H), 5.92 (m, 2H), 4.65 (d, 4H), 4.17 (q, 4H), 3.97 (t,2H), 3.67-3.55 (m, 2H), 3.42-3.30 (m, 2H), 2.95 (d, 4H), 1.23 (t, 6H),1.15 (t, 6H).

Example 2

[0114]

[0115]2-Ethoxy-3-(4-(4-(4-(2-ethoxy-2-hydroxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionicacid.

[0116] Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionate(0.210 mmol, 109 mg) was dissolved in ethanol (7 ml) by heating to 60°C. 1M NaOH (2.3 ml) was added and the reaction mixture was stirred at90° C. for 90 min. The reaction mixture was evaporated and 1 N HCl (6.5ml) and methylene chloride (30 ml) was added to the residue. The organicphase was collected and the aqueous phase was further extracted withmethylene chloride (2×25 ml). The combined organic phases were dried andevaporated to give the title compound in 87 mg (88%) yield. ¹H-NMR δ(CDCl₃) 9.55 (br. s, 2H), 7.17 (d, 4H), 6.80 (d, 4H), 5.91 (m, 2H), 4.65(d, 4H), 4.05 (m, 2H), 3.70-3.57 (m, 2H), 3.50-3.35 (m, 2H), 3.10-2.90(m, 4H), 1.21 (t, 6H).

Example 3

[0117]

[0118] Ethyl2-ethoxy-3-(4-(4-((4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-methyl)-benzyloxy)-phenyl)-propionate.

[0119] Was made as described under example 1, using1,4-benzenedimethanol instead of 2-buten-1,4-diol. Yield 1.29 g (60%).¹H-NMR δ (CDCl₃) 7.45 (s, 4H), 7.15 (d, 4H), 6.85 (d, 4H9, 5.04 (s, 4H),4.16 (q, 4H), 3.97 (t, 2H), 3.70-3.51 (m, 2H), 3.45-3.27 (m, 2H), 3.95(d, 4H), 1.4 (t, 6H), 1.15 (t, 6H).

Example 4

[0120]

[0121] Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-ynyloxy)-phenyl)-propionate.

[0122] Was made as described under example 1, using 2-butyn-1,4-diolinstead of 2-buten-1,4-diol. Yield 171 mg (65%). ¹H-NMR δ (CDCl₃) 7.17(d, 4H), 6.85 (d, 4H), 4.71 (s, 4H), 4.18 (q, 4H), 3.98 (t, 2H),3.70-3.53 (m, 2H), 3.45-3.27 (m, 2H), 2.96 (d, 4H), 1.25 (t, 6H), 1.18(t, 6H).

Example 5

[0123]

[0124]2-Ethoxy-3-(4-(4-((4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-methyl)-benzyloxy)-phenyl)-propionicacid.

[0125] Was made as described under Example 2. Yield 135 mg (86%). ¹H-NMRδ (CDCl₃) 7.37 (s, 4H), 7.08 (d, 4H), 6.80 (d, 4H), 4.98 (s, 4H), 3.99(m, 2H), 3.60-3.36 (m, 4H), 3.05-2.85 (m, 4H), 1.14 (t, 6H).

Example 6

[0126]

[0127]2-Ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-ynyloxy)-phenyl)-propionicacid.

[0128] Was made as described under Example 2. Yield 150 mg (100%).¹H-NMR δ (CDCl₃) 7.5 (br. s, 2H), 7.16 (d, 4H), 6.85 (d, 4H), 4.68 (s,4H9, 4.04 (m, 2H), 3.68-3.57 (m, 2H), 3.50-3.37 (m, 2H), 3.12-2.93 (m,4H), 1.17 (t, 6H).

What is claimed is:
 1. A compound of formula (I)

wherein R¹, R², R³ and R⁴ independently of each other are hydrogen,C₁₋₁₂-alkyl, C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl or C₁₋₆alkoxyC₁₋₆-alkyl, optionally substituted with oneor more halogen, hydroxy or amino; x₁, x₂, x₃ and x₄ independently ofeach other are carbon, oxygen, sulphur or nitrogen; Y is C₁₋₁₂-alkyl,C₂₋₁₂-alkenyl, C₂₋₁₂-alkynyl, aryl, aralkyl, alkylaralkyl, hereroaryl,heteroaralkyl, or alkylheteroaralkyl, optionally substituted with one ormore halogen, hydroxy or amino; and Ar¹ and Ar² independently of eachother are aryl or heteroaryl optionally substituted with one or morehalogen, hydroxy, amino, aminoalkyl, carboxyalkyl, C₁₋₆-alkyl orC₁₋₆-alkoxy; or a salt of any of the foregoing with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, including a racemic mixture, or any tautomeric forms.
 2. Thecompound according to claim 1, wherein said compound is Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionate,2-Ethoxy-3-(4-(4-(4-(2-ethoxy-2-hydroxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionicacid, Ethyl2-ethoxy-3-(4-(4-((4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-methyl)-benzyloxy)-phenyl)-propionate,Ethyl2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-ynyloxy)-phenyl)-propionate,2-Ethoxy-3-(4-(4-((4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-methyl)-benzyloxy)-phenyl)-propionicacid, or2-Ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-ynyloxy)-phenyl)-propionicacid; or a salt of any of the foregoing with a pharmaceuticallyacceptable acid or base, or any optical isomer or mixture of opticalisomers, including a racemic mixture, or any tautomeric forms.
 3. Apharmaceutical composition comprising, (i) as an active ingredient, acompound according to claim 1 or a pharmaceutically acceptable saltthereof and (ii) a pharmaceutically acceptable carrier or diluent.
 4. Acomposition according to claim 3 in unit dosage form, wherein saidcomposition comprises from about 0.05 to about 100 mg of the compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof.
 5. Apharmaceutical composition useful in the treatment and/or prevention ofconditions mediated by nuclear receptors, in particular the PeroxisomeProliferator-Activated Receptors (PPAR), the composition comprising, (i)as an active ingredient, a compound according to claim 1 or apharmaceutically acceptable salt thereof and (ii) a pharmaceuticallyacceptable carrier or diluent.
 6. A pharmaceutical composition useful inthe treatment and/or prevention of diabetes and/or obesity, thecomposition comprising, (i) as an active ingredient, a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof and(ii) a pharmaceutically acceptable carrier or diluent.
 7. Apharmaceutical composition according to claim 3 for oral, nasal,transdermal, pulmonary, or parenteral administration.
 8. A method forthe treatment of ailments, the method comprising administering to asubject in need thereof an effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt thereof.
 9. A method forthe treatment and/or prevention of conditions mediated by nuclearreceptors, in particular the Peroxisome Proliferator-Activated Receptors(PPAR), the method comprising administering to a subject in need thereofan effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 10. A method for the treatmentand/or prevention of diabetes and/or obesity, the method comprisingadministering to a subject in need thereof an effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof.
 11. The method according to claim 8, wherein the effectiveamount of the compound is in the range of from about 0.05 to about 100mg per day.